KR20040054557A - Cationic alkyd polyesters for medical applications - Google Patents

Abstract

PURPOSE: Provided are a medical apparatus, a composition and a microdispersion comprising a biodegradable and biocompatible synthetic polymer which has a low melting point and a low viscosity, is rapidly crystallized and can be biodegraded within 6 months. CONSTITUTION: The medical apparatus comprises a biodegradable and biocompatible synthetic polymer comprising a reaction product of a polybasic acid or its derivative, a monoglyceride and a cationic polyol. Preferably the polybasic acid or its derivative is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, suberic acid, sebacic acid, fumaric acid, maleic acid, maleic anhydride, mixture anhydride, an ester, an activated ester and an acid halide; the monoglyceride is selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyristoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol; and the cationic polyol is selected from the group consisting of N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol.

Description

Cationic alkyd polyesters for medical applications

The present invention relates to biodegradable and biocompatible polymers for use in pharmaceutical and medical applications.

Natural and synthetic polymers, including homopolymers and copolymers that are biocompatible and degradable in vivo, are known for use in the manufacture of medical devices that are implanted in human tissue and degrade over time. Examples of such medical devices include suture anchor devices, sutures, staples, surgical tacks, clips, plates, screws, drug delivery devices, anti-stick films and foams, and tissue adhesives.

Natural polymers may include joists, cellulose derivatives and collagen. Natural polymers are typically degraded by enzymatic degradation processes in the human body.

Synthetic polymers may include fatty polyesters, polyanhydrides and poly (orthoesters). Degradable synthetic polymers are typically degraded by hydrolysis mechanisms. Such degradable synthetic polymers include homopolymers such as poly (glycolide), poly (lactide), poly (e-caprolactone), poly (trimethylene carbonate) and poly (p-dioxanone), and poly (lac Copolymers such as tide coglycolide), poly (e-caprolactone coglycolide), poly (glycolide cotrimethylene carbonate), poly (alkylene diglycolate), and polyoxaesters. The polymer may be statistically a random copolymer, segmented copolymer, block copolymer or graft copolymer.

Alkyd based polyesters produced by polycondensation reactions of polyols, polyacids and fatty acids are used in the coating industry of various products including chemical resins, enamels, varnishes and paints. These polyesters are also used in the production of organized oils and emulsions for use as fat substitutes in the food industry.

The polymer has a low melting temperature and a low viscosity at the time of melting, whereby solvent-free processing techniques are applicable in the manufacture of medical devices and compositions and can be quickly crystallized and biodegradable within 6 months for use in drug delivery and medical devices. There is a strong demand for polymers. There is also a need for cationic polymers useful for delivering biologically active agents such as DNA, RNA, oligonucleotides, proteins, peptides and drugs to individuals in need thereof.

The present invention relates to medical devices and pharmaceutical compositions comprising biodegradable and biocompatible synthetic polymers comprising reaction products of polybasic acids or derivatives thereof, monoglycerides and cationic polyols.

Alkyd polymers are prepared by several known methods. For example, alkyd based polymers are described by Van Bemmelen, J. Prakt. Chem., 69 (1856) 84] was prepared by condensation of succinic anhydride with glycerol. “Fatty acid” methods [Parkyn, et al., Polyesters (1967), Iliffe Books, London, Vol. 2 and Patton, In: Alkyd Resins Technology, Wiley-Interscience New York (1962)] allow fatty acids, polyols and anhydrides to be mixed and reacted together. The "fatty acid-monoglyceride" method comprises a first step of esterifying a fatty acid with glycerol and adding acid anhydride when the first reaction is complete. The reaction mixture is then heated and causes a polymerization reaction. In the "oil-monoglyceride" method, the oil is reacted with glycerol to form a mixture of mono-, di- and triglycerides. This mixture is then polymerized by reacting with acid anhydride.

Biodegradable and biocompatible synthetic polymers used in the present invention are reaction products of polybasic acids or derivatives thereof, monoglycerides and cationic polyols and may be classified as cationic alkyd polyesters. Preferably, the polymers of the present invention are prepared by polycondensation reactions of polybasic acids or derivatives thereof, monoglycerides (monoglycerides comprising reactive hydroxy groups and fatty acid groups) and cationic polyols. Expected hydrolysis byproducts are glycerol, cationic polyols, dicarboxylic acids and fatty acids, all of which are biocompatible. The polymer comprises an aliphatic polyester backbone having pendant fatty acid ester groups. Long chain saturated fatty acids produce polymers that are polymerizable waxes that crystallize rapidly and exhibit relatively low melting points (eg, about 25-70 ° C.). As used herein, waxes are solid, low melt materials that are plastic at elevated temperatures and fluid when melted because of their relatively low molecular weight. Alternatively, the use of unsaturated or short chain fatty acids produces a liquid polymer. As used herein, a liquid polymer is a polymer that is liquid at room temperature, having a melting temperature of less than about 25 ° C., preferably less than about 20 ° C.

Polymerizable waxes and liquid polymers may be combined to form injectable microdispersions. The fine dispersion can be used to physically blend the liquid polymer of the invention with the finely divided polymerizable wax of the invention, or to form a large piece of polymeric wax suspension using the liquid polymer as a lubricant until the desired particle size distribution is obtained. It can form by grinding.

Generally, the polymeric wax will have an average particle diameter of less than about 500 microns and preferably less than 50 microns. At present, it is preferable to mix the finely divided polymerizable wax and the liquid polymer and to raise the temperature of the mixture to a temperature sufficient to melt the polymerizable wax (melt blending). Melt blending is preferred because it simplifies the mixing operation involved in the preparation of the fine dispersion. It is desirable to avoid excessive heating during melt blending to prevent transesterification of the polymer.

Monoglycerides usable in the preparation of the polymers used in the present invention are monostearoyl glycerol, monopalmitoyl glycerol, monomyricytoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinol Leoyl glycerol, monooleoyl glycerol and combinations thereof. Preferred monoglycerides include monostearoyl glycerol, monopalmitoyl glycerol and monomyricytoyl glycerol.

Polybasic acids that can be used include natural polyfunctional carboxylic acids such as succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid and sebacic acid; Hydroxy acids such as diglycolic acid, malic acid, tartaric acid and citric acid; And unsaturated acids such as fumaric acid and maleic acid. Polybasic acid derivatives include anhydrides such as succinic anhydride, diglycolic anhydride, glutaric anhydride and maleic anhydride, mixed anhydrides, esters, activated esters and acid halides. Preferred are the polyfunctional carboxylic acids listed above.

Cationic polyols that can be used include polyols and diols containing amine groups. Preferred diols include tertiary amine-containing diols such as N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol.

In the preparation of the polymers used in the present invention, particular chemical and mechanical properties required for the polymers for particular applications must be considered. For example, changes in chemical composition can change physical and mechanical properties, including absorption time. Copolymers can be prepared using mixtures of diacids, different monoalkanoyl glycerides, and different cationic polyols to satisfy a desired set of properties. Similarly, combinations of two or more cationic alkyd polyesters can be made to tailor properties for different applications.

Multifunctional monomers can be used to create crosslinked polymeric network structures. Alternatively, light crosslinking can be achieved by introducing double bonds using monoglycerides or diacids containing at least one double bond. Hydrogels that can be prepared in this way provide polymers with sufficient water solubility or swellability.

Functional polymers can be prepared by appropriately selecting monomers. Polymers having hydroxyl pendants can be synthesized using hydroxy acids, such as malic acid or tartaric acid, in the synthesis. Polymers having pendant amines, carboxyl or other functional groups can also be synthesized.

Various biologically active substances (hereinafter referred to as bioactive agents) can be covalently bound to these functional polymers by known coupling chemistry to obtain sustained release of the biologically active agents. As used herein, a bioactive agent includes a substance or material, such as a pharmaceutical compound, that has a therapeutic effect on a mammal.

In other embodiments, the polymers of the present invention may be endblocked in various ways to achieve the desired properties. End blocking reactions convert terminal and pendant hydroxyl groups and terminal carboxyl groups to other forms of chemical moieties. Typical end blocking reactions are alkylation and acylation reactions using conventional reagents such as alkyl, alkenyl or alkynyl halides and sulfonates, acid chlorides, anhydrides, mixed anhydrides, alkyl and aryl isocyanates and alkyl and aryl isothiocyanates Including but not limited to. End blocking reactions can impart new functionality to the polymers of the invention. For example, when endblocking these polymers using acryloyl or methacryloyl chloride, acrylate or methacrylate ester groups are produced, respectively, which are subsequently polymerized to form crosslinked network structures. Those skilled in the art will be able to ascertain the specific properties of the liquid polymer required for a particular purpose based on the advantages described herein and will readily be able to prepare a liquid polymer that provides these properties.

The polymerization reaction of the cationic alkyd polyester is preferably carried out under melt polycondensation conditions at elevated temperatures in the presence of an organometallic catalyst. The organometallic catalyst is preferably a tin-based catalyst, for example first tin octoate. The catalyst will preferably be present in a mixture in which the molar ratio of polyol and polycarboxylic acid to catalyst is in the range of about 15,000 / 1 to 80,000 / 1. The reaction is preferably carried out at a temperature of about 120 ° C. or higher. The higher the polymerization temperature, the higher the molecular weight of the copolymer, which may be desirable in many applications. The exact reaction conditions chosen will depend on a number of factors including the properties of the polymer desired, the viscosity of the reaction mixture and the melting temperature of the polymer. Preferred reaction conditions of temperature, time and pressure can be readily determined by analyzing these and other factors.

In general, the reaction mixture will be maintained at about 150 ° C. The polymerization reaction can proceed at this temperature until the desired molecular weight and conversion percentage for the copolymer is achieved (typically about 15 minutes to 24 hours). Increasing the reaction temperature generally reduces the reaction time required to achieve a particular molecular weight.

In another embodiment, copolymers of cationic alkyd polyesters are prepared by forming a cationic alkyd polyester prepolymer polymerized under melt polycondensation conditions and then adding at least one aliphatic polyester monomer or aliphatic polyester prepolymer. can do. The mixture is then copolymerized with the aliphatic polyester monomer under the desired temperature and time conditions. Aliphatic polyester monomers for this embodiment include glycolide, L-lactide, D-lactide, meso-lactide, rac-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1 , 4-dioxanone, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and substituted derivatives thereof.

The molecular weight of the prepolymer and its composition may vary depending on the desired properties that the prepolymer imparts to the copolymer. Those skilled in the art will appreciate that the cationic alkyd polyester prepolymers described herein may be prepared from mixtures of one or more monoglycerides, dioxycarboxylic acids or cationic polyols.

The polymers, copolymers, and combinations of the present invention can be crosslinked to affect mechanical properties. Crosslinking can be accomplished by adding crosslinking enhancers, spinning agents (eg gamma-spinning agents) or a combination of the two. In particular, crosslinking can be used to control the amount of expansion experienced by the material of the present invention in water.

One of the advantageous properties of the cationic alkyd polyesters of the present invention is that the ester bonds in the alkyd blocks are hydrolytically unstable, thus the polymer is biodegradable because it readily degrades into small segments when exposed to moist human tissue. . In this respect, it is anticipated that co-reactants may be incorporated into the reaction mixture of polybasic acids, monoglycerides and cationic polyols for the formation of cationic alkyd polyesters, although the reaction mixtures are non-degradable It is preferred not to contain any co-reactant concentration which results in. Preferably, the reaction mixture is substantially free of any such co-reactants when the resulting polymer is non-degradable.

In one embodiment of the invention, the cationic alkyd polyesters of the invention can be used as pharmaceutical carriers in drug delivery substrates. Solid cationic alkyd polyester waxes can be used to coat or encapsulate the bioactive agent. Alternatively, an effective amount of the bioactive agent can be mixed with injectable microdispersions of the polymeric wax and liquid polymer. Such microdispersions are particularly suitable for labile drugs such as proteins.

The range of bioactive agents that can be used with the polymers of the present invention is very wide. Generally, biologically active agents that can be administered through the pharmaceutical compositions of the invention include anti-infective agents such as antibacterial and antiviral agents; Analgesics and analgesic combinations; Loss of appetite; helminthic; Anti-arthritis agents; Anti-asthmatic agents; Anticonvulsants; Antidepressants; Antidiuretics; Anticoagulant; Antihistamines; Anti-inflammatory agents; Antimigraine agents; Antiemetic agent; Anticancer agents; Anti-Parkinson drugs; Antipruritic agents; Antipsychotics; fever remedy; Anticonvulsants; Anticholinergic agents; Sympathetic stimulants; Xanthine derivatives; Cardiovascular and antiarrhythmic agents, including calcium channel blockers such as pindolol and beta-blockers; Antihypertensives; diuretic; Vasodilators including general coronary, peripheral and cerebral; Central nervous system stimulant; Cough and cold preparations, including nasal decongestants; Hormones such as estradiol and other steroids, including corticosteroids; sleeping pills; Immunosuppressants; Muscle relaxants; Parasympathetic blockers; Mental stimulant; sedative; Nerve stabilizers; Natural or genetically engineered proteins, growth factors, polysaccharides, glycoproteins or lipoproteins; Oligonucleotides; Antibodies; antigen; Cholinergic agents; Chemotherapy agents; styptic; Coagulant; Radioactive reagents and cell proliferation inhibitors.

Rapamycin, risperidone, and erythropropane are several bioactive agents that can be used in the drug delivery substrate of the present invention.

The drug delivery substrate may be administered in any suitable dosage form such as oral, parenteral, lung, oral, nasal, eye, topical, vaginal route or suppository. Bioerodible particles, ointments, gels, creams and similar soft dosage forms suitable for administration via this route may also be prepared. Other dosage forms (eg transdermal) and composition formulations (eg more rapid transdermal formulations) are also within the scope of the present invention.

Parenteral administration of the bioerodible compositions of the invention may be by subcutaneous or intramuscular injection. Bioactive agents can be encapsulated in particles made of solid polymers. Alternatively, the parenteral formulation of the copolymer can be prepared by mixing one or more pharmaceutical formulations with a liquid copolymer or microdispersion. Other suitable parenteral additives may be formulated with the copolymer and the pharmaceutical active. However, if water is to be used, it must be added immediately before administration. Bioerodible ointments, gels or creams may be injected as such or in combination with one or more suitable accessory ingredients described below. Parenteral delivery is preferred for administration of proteinaceous drugs such as growth factors, growth hormones, and the like.

Bioerodible ointments, gels and creams of the present invention will include an ointment, gel or cream base comprising one or more copolymers described herein and selected bioactive agents. Bioactive agents present in liquids, finely divided solids or any other physical form are dispersed in ointments, gels or cream bases. Typically the composition optionally comprises one or more other ingredients such as nontoxic auxiliary substances such as colorants, diluents, odorants, carriers, excipients, stabilizers and the like.

The amount and shape of the copolymers incorporated into parenteral ointments, gels, creams, and the like may vary. High molecular weight polymers are used for high viscosity compositions. If a low viscosity composition is desired, low molecular weight polymers can be used. The product may contain a combination of liquid or low melting copolymers to provide the desired release profile or concentration for a given formulation.

Although not essential for topical or transdermal administration of many drugs, it may be desirable in some cases to administer a skin penetration enhancer with the drug. Any number of skin penetration enhancers known in the art can be used. Examples of suitable enhancers include dimethylsulfoxide (DMSO), dimethylformamide (DMF), N, N-dimethylacetamide (DMA), decylmethylsulfoxide, ethanol, eucalyptol, lecithin and 1-N-dodecylcycleaza Cycloheptan-2-one is included.

Depending on the dosage form, the pharmaceutical compositions of the invention may be administered in different ways, i.e. parenterally, topically, and the like. Preferred dosage forms are liquid dosage forms that can be administered parenterally.

The amount of bioactive agent will vary depending on the particular drug used and the medical treatment conditions. Typically, the amount of drug is about 0.001 to about 70%, more typically about 0.001 to about 50%, most typically about 0.001 to about 20% by weight of the substrate.

The amount and form of the cationic alkyd polyester incorporated into the parenteral formulation will depend upon the desired release profile and amount of the drug used. The product may contain a combination of polymers to provide the desired release profile or concentration for a given formulation.

Cationic alkyd polyesters are slowly degraded primarily by hydrolysis when in contact with body fluids including blood and the like, and the dispersed drug is released simultaneously for a prolonged or prolonged time compared to release from isotonic saline solutions. This allows for long term delivery of an effective amount of drug (eg about 1 to about 2,000 mg / kg / hour, preferably about 2 to about 800 mg / kg / hour, or 0.0001 to 10 mg / kg / hour). Dosage forms may be administered as needed depending on the subject to be treated, the extent of pain, the judgment of the prescribing physician, and the like.

Separate formulations of drug and cationic alkyd polyesters can be tested in suitable in vitro and in vivo models to achieve the desired drug release profile. For example, drugs are prepared and administered orally to animals. The drug release profile is then observed by any suitable means, such as taking a blood sample at a specific time and analyzing the sample for drug concentration. Those skilled in the art will be able to produce various formulations according to the above or similar procedures.

In a further aspect of the invention, polymers and combinations thereof can be used in the field of tissue engineering, for example as support for cells or as delivery carriers for cells. Suitable tissue scaffolds structures are known in the art, including prosthetic articular cartilage described in US Pat. No. 5,306,311, porous biodegradable scaffolds described in WO 94/25079, and International Publications. Implants such as those previously passed by blood vessels of WO 93/08850 (all of which are incorporated herein by reference). Methods for seeding and / or culturing cells in tissue scaffolds are known to those skilled in the art, including EP 0 422 209 B1, WO 88/03785, WO 90 / 12604 and WO 95/33821, all of which are incorporated herein by reference in their entirety.

The polymer of the present invention can be melt treated in a number of ways to produce a number of useful devices. These polymers can be sprayed or press molded to produce implantable medical and surgical devices, in particular wound closure devices. Preferred wound closure devices are surgical clips, staples and sutures.

Alternatively, the cationic alkyd polyester can be extruded to produce filaments. The filaments thus prepared can be made into sutures or ligations by known techniques and attached to surgical needles for packaging and sterilization. The polymers of the present invention may be processed into single filament or composite filament yarns and wovens or knits and formed into sponges or gauze, or other press-molded structures (structures have high tensile strength and the desired degree of elasticity and / or ductility Preferably a human or animal body prosthetic device. Nonwoven sheets can also be produced and used as described above. Useful embodiments include taped and sustained tubes including branching tubes for arterial, venous or intestinal repair, neural junctions, tendon junctions, damaged external scratches, especially severe scratches, and where skin and subcutaneous tissue are damaged or surgically separated It includes a sheet to be.

In addition, the polymer can be cast to form a film useful as an anti-adhesion barrier in sterilization. Other processing techniques for the polymers of the present invention include solvent casting, particularly where drug delivery substrates are desired. More specifically, surgical and medical uses of the filaments, films, and cast products of the present invention include, without limitation, knitted, woven or nonwoven and cast products, including burn dressings, hernia patches, meshes, drug containing dressings, facial prostheses. , Gauze, textiles, sheets, felt or liver congestion sponges, gauze bandages, arterial grafts or substitutes, bandages for skin surfaces, suture knot clips, orthopedic pins, clamps, screws, plates, clips (E.g. for vena cava), staples, hooks, buttons, snaps, skeletal substitutes (e.g. mandibular prostheses), intrauterine devices (e.g. sperm devices), drainage or test tubes or capillaries, surgical instruments, vascular implants or Supports such as stents or grafts or combinations thereof, scaffolds, extracorporeal intubation for kidney and heart-pulmonary organs, supports for cells in the field of artificial skin and tissue engineering Not limited.

In another embodiment, the smoothness of the coated surface is improved by applying the surface of the medical device using a cationic alkyd polyester polymer. The polymer may be coated using conventional techniques. For example, the polymer is dissolved in a dilute solution of volatile organic solvent such as acetone, methanol, ethyl acetate or toluene, and then the product is immersed in solution to apply the surface. Once the surface is applied, the surgical product is removed from the solution and dried at elevated temperature until the solvent and any residual reactants are removed.

In another embodiment of the present invention, solid waxes derived from cationic alkyd polyesters can be used to protectively apply particulates encapsulating the bioactive agent (s). This will help to provide an additional barrier for the sustained release of the drug.

Injectable microdispersions can be used for a variety of soft tissue repairs and dilatations. For example, microdispersions include, but are not limited to, scar cover, depression filling, asymmetric reinforcement of facial atrophy, secondary sagittal syndrome, facial lipodystrophy and aging wrinkle covers, and dilatation of facial ridges (eg, lips, jaw, etc.) It can be used for facial tissue repair or augmentation, including. In addition, these injectable microdispersions are used to revive or improve sphincter function, such as in the treatment of stress incontinence. Other uses of these injectable microdispersions may include the treatment of bladder ureter reflux (incomplete function of the ureter inlet of a child) in which the microdispersion is administered by intra-urinary injection as a general purpose filler in the human body.

Surgical uses of injectable biodegradable microdispersions include facial contouring, such as distortion or glacial wrinkling, acne scars, cheek depressions, lip axis or periphery wrinkles, marionette wrinkles or lateral transverse union wrinkles, forehead Wrinkles, crow's feet or crow's feet, deep micro or nasolabial folds, micro lines, facial scars, lips, etc .; Periuretic injection, including injection below the urethra along the urethra and submucosa along the urethra to the external sphincter; Urethral injections to prevent ureter reflux; Injection into the gastrointestinal tract tissue to swell the tissue to prevent reflux; Injection for internal or external sphincter junction and enlarged lumen; Intraocular injection for replacement of the vitreous fluid and maintenance of intraocular pressure during retinal detachment; Injection into an anatomical conduit to temporarily turn off the exit to prevent reflux or transmission of infection; Laryngeal recovery after surgery or atrophy; And any other soft tissue that can expand for cosmetic or therapeutic effects. Surgical specialists who will use such products include plastic reconstructive surgeons; dermatologist; Facial reconstructive surgeons; Plastic surgeon; ophthalmologist; And any other physician who is qualified to use such a product.

In addition, to facilitate administration and treatment of the microdispersion of the invention to a patient, pharmaceutically active compounds or adducts may be administered together. Pharmaceutically active agents that can be administered with the microdispersions of the invention include anesthetics such as lidocaine; And anti-inflammatory agents such as cortisone.

The fine dispersions can be administered by syringe and needle or by various devices. The fine dispersion may also be commercially available in the form of a kit consisting of a device containing the fine dispersion. The apparatus has an outlet for the microdispersion, an ejector for discharging the microdispersion and a hollow tube tube mounted at the outlet for administering the microdispersion to the animal.

Dosage forms for the microdispersions of the invention are sustained release parenteral bioerodible ointments, gels, creams and similar soft dosage forms.

The embodiments described below are for illustrative purposes only and do not limit the scope of the claims in any way. Those skilled in the art will readily recognize many additional embodiments within the scope and spirit of the invention.

EXAMPLE

Example 1

Synthesis of Poly (monostearoylglyceride co succinate) solids containing 5% N-methyldiethanolamine

40.3 g (112.5 mmol) monostearoyl glycerol, 12.5 g (125 mmol) succinic anhydride and 1.5 g (12.5 mmol) N-methyldiethanolamine in a single neck, dried 100 ml round bottom flask, Add with 1 tin octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. When the solution crystallizes, it is degassed and gas fragments are removed. The polymer is a brown solid.

Example 2

Synthesis of Poly (monostearoylglyceride co succinate) solids containing 10% N-methyldiethanolamine

25 μl of first tin in 35.9 g (100 mmol) monostearoyl glycerol, 12.5 g (125 mmol) and 3.0 g (25 mmol) N-methyldiethanolamine in a single neck dried 100 mL round bottom flask Add with octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. When the solution crystallizes, it is degassed and gas fragments are removed. The polymer is a brown solid.

Example 3

Synthesis of Poly (Monooleoylglyceride Co Succinate) Liquid Containing 5% N-Methyldiethanolamine

25 μl of the first monooleoyl glycerol, 12.5 g (125 mmol) succinic anhydride and 1.5 g (12.5 mmol) N-methyldiethanolamine in a single neck dried 100 ml round bottom flask Add with tin octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. The polymer is a brown transparent viscous liquid.

Example 4

Synthesis of Poly (Monooleoylglyceride Co Succinate) Liquid Containing 10% N-methyldiethanolamine

25 μl of the first tin of 36.7 g (100 mmol) glyceryl monooleate, 12.5 g (125 mmol) and 3.0 g (25 mmol) N-methyldiethanolamine in a single neck dried 100 mL round bottom flask Add with octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. The polymer is a brown transparent viscous liquid.

Example 5

Synthesis of Poly (monostearoylglyceride cosuccinate) solids containing 5% (3-dimethylamino-1,2-propanediol)

Single neck dried 100 ml round bottom flask with 40.3 g (112.5 mmol) monostearoyl glycerol, 12.5 g (125 mmol) succinic anhydride and 1.5 g (12.5 mmol) 3-dimethylamino-1,2-propanediol To 25 μl of first tin octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. When the solution crystallizes, it is degassed and gas fragments are removed. The polymer is a brown solid.

Example 6

Synthesis of Poly (monostearoylglyceride cosuccinate) solids containing 10% (3-dimethylamino-1,2-propanediol)

35.9 g (100 mmol) of monostearoyl glycerol, 12.5 g (125 mmol) and 3.0 g (25 mmol) of 3-dimethylamino-1,2-propanediol in a single neck dried 100 ml round bottom flask Add with μl of first tin octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. When the solution crystallizes, it is degassed and gas fragments are removed. The polymer is a brown solid.

Example 7

Synthesis of Poly (Monooleoylglyceride Co Succinate) Liquid Containing 5% 3-dimethylamino-1,2-propanediol

Single neck dried 100 ml round bottom flask with 40.1 g (112.5 mmol) glyceryl monooleate, 12.5 g (125 mmol) succinic anhydride and 1.5 g (12.5 mmol) 3-dimethylamino-1,2-propanediol To 25 μl of first tin octoate. Insert the stir bar and attach the nitrogen inlet tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. The polymer is a brown transparent viscous liquid.

Example 8

Synthesis of Poly (Monooleoylglyceride Cosuccinate) Liquid Containing 10% 3-dimethylamino-1,2-propanediol

25 μl of 36.7 g (100 mmol) glycerol monooleate, 12.5 g (125 mmol) and 3.0 g (25 mmol) 3-dimethylamino-1,2-propanediol in a single neck dried 100 mL round bottom flask Add with 1st tin octoate. Insert the stirring bar and attach the nitrogen injection induction tube. The reaction flask is placed in an oil bath at room temperature to start a nitrogen blanket. The temperature is raised to 150 ° C. and maintained for 6 hours. After 6 hours, the flask is removed from the oil bath and cooled to room temperature. The polymer is a brown transparent viscous liquid.

According to the present invention, polymers for use in drug delivery and medical devices are obtained, having low melting temperatures and low viscosities upon melting, which can be quickly crystallized and biodegradable within 6 months in the manufacture of medical devices and compositions, Cationic polymers are obtained that are useful for delivering a bioactive agent to a subject.

Claims (38)

A medical device comprising a biodegradable and biocompatible synthetic polymer comprising a reaction product of a polybasic acid or derivative thereof, monoglycerides and cationic polyols. The polybasic acid or derivative thereof is succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric anhydride, glutaric anhydride, adipic acid, pimelic acid, water A medical device selected from the group consisting of vermic acid, sebacic acid, fumaric acid, maleic acid, maleic anhydride, mixed anhydrides, esters, activated esters and acid halides. The monoglyceride of claim 1, wherein the monoglycerides are monostearoyl glycerol, monopalmitoyl glycerol, monomyricitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and mono A medical device selected from the group consisting of oleoyl glycerol. The medical device according to claim 3, wherein the polybasic acid derivative is succinic anhydride. The medical device of claim 3 wherein the polybasic acid is succinic acid. The medical device of claim 1 wherein the cationic polyol is selected from the group consisting of N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol. The medical device of claim 1 wherein the polymer is a branched chain. The method of claim 1, wherein the copolymer is at least two polybasic acids selected from the group consisting of monoglycerides, cationic polyols, and succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, and diglycolic acid anhydride. A medical device comprising the reaction product of a derivative. The method of claim 1 wherein the copolymer is a polybasic acid or derivative thereof, cationic polyol, and monostearoyl glycerol, monopalmitoyl glycerol, monomyricytoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl A medical device comprising a reaction product of two or more monoglycerides selected from the group consisting of glycerol, monolinoleoyl glycerol and monooleoyl glycerol. The medical device of claim 1, wherein the copolymer comprises a reaction product of monoglycerides, polybasic acids or derivatives thereof, N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol. The medical device of claim 1, further comprising an effective amount of a bioactive agent. The medical device of claim 1 further comprising a terminal blocking moiety selected from the group consisting of alkyl, alkenyl, alkynyl, acrylate, methacrylate, amine, isocyanate and isothiocyanate. 2. Glycolide, L-lactide, D-lactide, meso-lactide, rac-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,4-di Medical device further comprising an aliphatic polyester made from a monomer group selected from the group consisting of oxanone, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one and substituted derivatives thereof . The medical device of claim 1 comprising a coating of polymer. The method of claim 14, wherein the glycolide, L-lactide, D-lactide, meso-lactide, rac-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,4-di Medical device further comprising an aliphatic polyester made from a monomer group selected from the group consisting of oxanone, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one and substituted derivatives thereof . The method of claim 1, wherein the sutures, stents, vascular grafts, stent-graft combinations, meshes, tissue engineering scaffolds, pins, clips, staples, films, sheets, foams, A medical device selected from the group consisting of anchors, screws and plates. The device of claim 1, wherein the polymer is a polymerizable wax having a melting point of about 25 to about 70 ° C. 3. The device of claim 1, wherein the polymer is a liquid polymer having a melting point of less than about 25 ° C. 3. A composition comprising a polymer comprising a reaction product of an effective amount of a bioactive agent and a polybasic acid or derivative thereof, a monoglyceride and a cationic polyol. The method of claim 19, wherein the polybasic acid or derivative thereof is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, water A composition selected from the group consisting of vermic acid, sebacic acid and derivatives thereof. 20. The monoglyceride of claim 19, wherein the monoglycerides are monostearoyl glycerol, monopalmitoyl glycerol, monomyricitoyl glycerol, monocaproyl glycerol, monodecanoyl, monolauroyl glycerol, monolinoleoyl glycerol and monooles. A composition selected from the group consisting of oil glycerol. The composition of claim 21 wherein the polybasic acid derivative is succinic anhydride. The composition of claim 21 wherein the polybasic acid is succinic acid. 20. The composition of claim 19, wherein the polymer is branched chain. The method of claim 19, wherein the copolymer is at least two polybasic acids selected from the group consisting of monoglycerides, cationic polyols, and succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, and diglycolic acid anhydride. A composition comprising the reaction product of a derivative. The method of claim 19, wherein the copolymer is a polybasic acid or derivative thereof, cationic polyols, and monostearoyl glycerol, monopalmitoyl glycerol, monomyricytoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl A composition comprising the reaction product of two or more monoglycerides selected from the group consisting of glycerol, monolinoleoyl glycerol and monooleoyl glycerol. 20. The composition of claim 19, wherein the copolymer comprises a reaction product of monoglycerides, polybasic acids or derivatives thereof, N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol. The antimicrobial agent of claim 19, wherein the bioactive agent is an anti-infective, analgesic, anorexia, antiparasitic, anti-arthritis, anti-asthmatic, anticonvulsant, antidepressant, antidiuretic, anti-diabetic, antihistamine, anti-inflammatory, anti-migraine, anti-emetic Anticancer, antiparkinsonian, antipruritic, antipsychotic, antipyretic, anticonvulsant, anticholinergic, sympathomimetic, xanthine derivatives, calcium channel blocker, beta-blockers, antiarrhythmics, antihypertensives, diuretics, vasodilators, CNS stimulants, nasal decongestants, hormones, steroids, sleeping pills, immunosuppressants, muscle relaxants, parasympathetic nerve blockers, psychostimulants, sedatives, nerve stabilizers, natural or genetically engineered proteins, growth factors, polysaccharides, glycoproteins or lipo Proteins, oligonucleotides, antibodies, antigens, cholinergic agents, chemotherapy agents, hemostatic agents, coagulants, radioactive reagents and cell proliferation inhibitory Composition is selected from the group consisting of. The method of claim 19, wherein the glycolide, L-lactide, D-lactide, meso-lactide, rac-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,4-di And an aliphatic polyester prepared from a monomer group selected from the group consisting of oxanone, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one and substituted derivatives thereof. 20. The composition of claim 19, wherein the polymer is a polymeric wax having a melting point of about 25 to about 70 ° C. 20. The composition of claim 19, wherein the polymer is a liquid polymer having a melting point of less than about 25 ° C. A fine dispersion comprising a combination of polymerizable waxes and liquid polymers, wherein the polymerizable waxes and liquid polymers comprise reaction products of polybasic acids or derivatives thereof, monoglycerides and cationic polyols. 33. The method of claim 32, wherein the polybasic acid or derivative thereof is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric anhydride, glutaric anhydride, adipic acid, pimelic acid, water Fine dispersions selected from the group consisting of vermic acid, sebacic acid, fumaric acid, maleic acid, maleic anhydride, mixed anhydrides, esters, activated esters and acid halides. 33. The monoglyceride of claim 32, wherein the monoglycerides are monostearoyl glycerol, monopalmitoyl glycerol, monomyricitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and mono Microdispersion selected from the group consisting of oleoyl glycerol. The fine dispersion of claim 34, wherein the polybasic acid derivative is succinic anhydride. The fine dispersion of claim 34, wherein the polybasic acid is succinic acid. The fine dispersion of claim 34, wherein the cationic polyol is selected from the group consisting of N-methyl diethanolamine and 3-dimethylamino-1,2-propanediol. 33. The microdispersion of claim 32, further comprising an effective amount of a bioactive agent.